Human papillomavirus (HPV)-immortalized cervical epithelial cells and HPV-- positive cervical carcinomas are being evaluated as a model of lymphokine modulation of epithelial cell sensitivity to natural immunologic cytotoxicity. The sensitivity of human cervical epithelial cells, immortalized by transfection with HPV-16 DNA, to lysis by NK and LAK lymphocytes, was evaluated at progressive stages of transformation. Both early (10-20 weeks) and late (>30 weeks) passage HPV-16-immortalized cells were resistant to NK but sensitive to LAK lymphocyte cytotoxicity at lymphocyte to cervical cell ratios ranging from 1:1 to 50:1 in a 4 hr 51Cr release assay. Treatment of early passage HPV-16-DNA-immortalized cells with 2.5 units/ml of the NK lymphocytotoxicity sensitizing lymphokine, leukoregulin, for 1 hr, induced modest sensitivity to NK (P <.05) but markedly up-regulated LAK sensitivity two- to threefold. At the later passages, leukoregulin up-regulation of sensitivity to NK was lost but remained to LAK lymphocytotoxicity. Similarly, an HPV-16-positive human cervical carcinoma cell line, QGU, was also resistant to NK and sensitive to LAK lymphocytotoxicity; leukoregulin failed to confer sensitivity to the NK-resistant QGU tumor cells and increased their sensitivity to LAK lymphocytotoxicity 1.5 to 2-fold. Although the HPV-immortalized cervical cells containing integrated HPV-16 DNA are not tumorigenic, they mimic the response of established HPV-16-positive cervical carcinoma cells. HPV-16-immortalized cervical epithelial cells provide a useful model for the study of cytokine modulation of dysplastic and neoplastic cervical epithelial cell sensitivity to natural lymphocytotoxicity.